Malignant melanoma (melanoma) is a malignant tumor in which melanocytes, which are melanin-producing cells, become cancerous. It is curable by early detection, but the five-year survival rate in a case where distant metastasis has occurred is as low as about 10% and an effective therapy has not yet been established (for example, refer to NPLs 1 and 2). A BRAFV600E gene mutation has been confirmed in about 60% to 70% or more of cases. By BRAF (MAPKKK of MAPK pathway), downstream MEK (MAPKK of MAPK pathway) is phosphorylated and activated, and by the activated MEK, further downstream ERK (MAPK of MAPK pathway) is phosphorylated and activated, and therefore, many proteins associated with proliferation, survival, invasion, and metastasis are activated (for example, refer to NPL 3). BRAF being constantly and strongly activated by BRAFV600E mutation is one of the causes of melanoma. Clinical trials using a selective inhibitor (PLX4032, vemurafenib) of mutant BRAF are being conducted currently, and a high response rate has been confirmed. It has been reported that the effect of BRAF inhibitors becomes limited, as drug resistance against it occurs due to various mechanisms such as expression of splicing variants of the BRAF gene and expression of hepatocyte growth factor (HGF) secreted by interstitial cells (for example, refer to NPLs 4 to 6).
Epithelial Mesenchymal Transition (EMT) is known as one of the causes of epithelial cancer acquiring metastatic ability. EMT is a phenomenon in which epithelial cells acquire the trait of mesenchymal cells, and it is known that when EMT occurs, the expression level of E-cadherin, which is an epithelial cell adhesion molecule, is decreased. In addition, it has been revealed that EMT is regulated by a transcription factor such as Snail, Slug, and Twist, and it is known that these factors regulate expression of E-cadherin and the like, by which EMT is induced (for example, refer to NPL 7).
In melanoma, many expressions of EMT-implicated genes are altered in a case where metastasis has occurred, and it has been suggested that an enhanced EMT program is one of the causes of metastasis (for example, refer to NPL 8). In addition, in melanoma having a BRAF mutation, expression of transcription factors such as Zeb 1 and Twist 1 are induced by constitutive activation of BRAF, inhibition of E-cadherin expression by these factors, and EMT-like phenomenon that melanoma exacerbation is caused Have been confirmed. (for example, refer to NPL 9). It has been reported that the expression level of E-cadherin decreased in many melanomas, and the recurrence rate significantly increased in cases where the expression of E-cadherin is decreased (for example, refer to NPL 10). These findings suggest an association between decreased expression of E-cadherin and enhanced malignancy of melanoma.
EMT is an essential phenomenon not only in cancer but also during early embryonic development, and is involved in gastrulation and neural crest cell differentiation. Neural crest cells induce EMT in a part of the dorsal neural tube, separated from the epithelial tissue, and therefore acquire migration ability, and then differentiate into cells of the peripheral nervous system, glial cells, satellite cells, melanocytes, odontoblasts, craniofacial cartilage, and the like. Also by EMT of neural crest cells, decreased expression of E-cadherin is induced by transcription factors such as Snail, Slug, and Twist (for example, refer to NPLs 7 and 11).